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WO2023009744A1 - Méthode de réduction d'une inflammation chronique systémique liée à l'âge - Google Patents

Méthode de réduction d'une inflammation chronique systémique liée à l'âge Download PDF

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Publication number
WO2023009744A1
WO2023009744A1 PCT/US2022/038704 US2022038704W WO2023009744A1 WO 2023009744 A1 WO2023009744 A1 WO 2023009744A1 US 2022038704 W US2022038704 W US 2022038704W WO 2023009744 A1 WO2023009744 A1 WO 2023009744A1
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Prior art keywords
subject
composition
iage
glucan
beta
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PCT/US2022/038704
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English (en)
Inventor
El Hadji M. DIOUM
Yifang Chu
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Quaker Oats Co
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Quaker Oats Co
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Priority to CN202280053131.9A priority Critical patent/CN117715635A/zh
Priority to CA3224611A priority patent/CA3224611A1/fr
Priority to MX2024001124A priority patent/MX2024001124A/es
Priority to AU2022320711A priority patent/AU2022320711A1/en
Priority to EP22757754.1A priority patent/EP4376825A1/fr
Publication of WO2023009744A1 publication Critical patent/WO2023009744A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
    • A61K31/716—Glucans
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A61K31/196—Carboxylic acids, e.g. valproic acid having an amino group the amino group being directly attached to a ring, e.g. anthranilic acid, mefenamic acid, diclofenac, chlorambucil
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]

Definitions

  • the present disclosure relates generally to the reduction of age-related chronic inflammation. More specifically, the present disclosure relates to a method of reducing systemic chronic inflammation by administering an effective amount of b- glucan, avenanthramides, or other phenolics.
  • SCI Systemic chronic inflammation
  • the implications of systemic chronic inflammation can be severe and include elevated risk of type 2 diabetes, hypertension, cardiovascular disease, chronic kidney disease, cancer, depression, neurodegenerative and autoimmune diseases, and osteoporosis.
  • Inflammation is a highly conserved defensive mechanism capable of eliminating microorganisms and repairing tissue. It is characterized by the activation of immune and non-immune cells that provide surveillance and protection against a full spectrum of microorganisms and toxic insults. Normal inflammatory responses are represented by acute and time-limited upregulation of the innate inflammatory response. Typically, this acute innate immune response is short and self-resolves once the threat has been eliminated.
  • SCI acute innate inflammatory response
  • SCI or “inflamrmaging” is a major characteristic of the aging process. It is believed that SCI is initiated by unresolved triggers of acute inflammation or physical, chemical, or metabolic noxious stimuli (i.e., “sterile” agents), released by damaged cells or environmental insults that are generally called damage-associated molecular patterns (DAMP).
  • DAMPS damage-associated molecular patterns
  • a novel metric for SCI was developed from a ten-year project across 1 ,000 subjects at Stanford University called the 1 ,000 Immunomes Project (1 KIP). This metric was derived from a deep learning algorithm applied to immune protein serum biomarkers.
  • the Stanford 1 KIP focused on global analysis of the immune system and utilized state-of-the-art deep learning tools to construct a scoring system for age- related chronic inflammation (Inflammatory Age®, iAge®) which predicted multi morbidity, premature cardiovascular aging, immunological decline, frailty and all cause mortality.
  • Some of the biomarkers of iAge® identified in the Stanford 1 KIP include CCL11 (Eotaxin), Interferon-gamma (IFN-y), Growth Regulated Oncogene- alpha (Gro-oc), Monokine Induced by Gamma Interferon (CXCL9) and TNF-related Apoptosis Inducing Ligand (TRAIL).
  • CCL11 Eotaxin
  • IFN-y Interferon-gamma
  • Ga-oc Growth Regulated Oncogene- alpha
  • CXCL9 Monokine Induced by Gamma Interferon
  • TRAIL TNF-related Apoptosis Inducing Ligand
  • the method to reduce SCI includes administering to a subject an effective amount of a composition that includes selected ingredients to reduce the expression level of biomarkers associated with systemic chronic inflammation.
  • the method takes advantage of the discovery of biomarkers that correlate with increased inflammation.
  • Initial SCI biomarkers were identified based on those used in an algorithm called iAge® that calculates a biological age of a subject based on the levels of certain SCI biomarkers. For example, a person having a chronological age of 50 may have a biological age of less than 50 or greater than 50 depending on the subject’s expressed levels of certain SCI biomarkers. Accordingly, while the chronological age cannot change, the biological age of a subject can fluctuate up or down over time depending on a variety of variables.
  • the composition may be provided as a powder capable of being encapsulated such as in a biodegradable capsule.
  • the composition may be provided as a loose powder capable of being added or incorporated into foodstuff or beverages.
  • the composition may be configured to be ingested by a subject.
  • Fig. 1 A is a graph comparing the baseline (day 0) iAge® to the week two iAge® for the treated group.
  • Fig. 1 B is a graph comparing the baseline iAge® to the week two iAge® for the untreated group.
  • Fig. 1 C is a graph comparing the CCL11 levels at baseline to the week two CCL11 levels for the treated group.
  • Fig. 1 D is a graph comparing the CCL11 levels at baseline to the week two CCL11 levels for the untreated group.
  • Fig. 2A is a graph showing four variables are useful predictors to identify responders and non-responders within the treated group.
  • Fig. 2B is a graph showing that of the four variables, two are negative predictors and two are positive predictors.
  • Fig. 2C is a graph showing that none of an initial 39 variables appear to be useful to predict responders and non-responders within the untreated group.
  • Fig. 3A is a graph showing the comparison of iAge® at baseline to week two for the treated group having an initial baseline iAge® score less than 49.6.
  • Fig. 3B is a graph showing the comparison of iAge® at baseline to week two for the treated group having an initial baseline iAge® score greater than 49.6.
  • Fig. 3C is a graph comparing the iAge® at baseline to week two for the untreated group having an initial baseline iAge® score less than 49.6
  • Fig. 3D is a graph comparing of iAge® at baseline to week two for the untreated group having an initial baseline iAge® score greater than 49.6.
  • Fig. 3E is a graph comparing the CCL11 level at baseline to week two for the treated group having an initial baseline iAge® score is less than 49.6.
  • Fig. 3F is a graph comparing the CCL11 level at baseline to week two for the treated group having an initial baseline iAge® score is greater than 49.6.
  • Fig. 3G is a graph comparing the CCL11 level at baseline to week two for the untreated group having an initial baseline iAge® score is less than 49.6
  • Fig. 3H is a graph comparing the CCL11 level at baseline to week two for the untreated group having an initial baseline iAge® score is greater than 49.6.
  • Fig. 4 is a graph showing the treated (T) and untreated (U) groups subdivided into high/low baseline iAge® using a cut-off of 49.6 years and high/low baseline LDL levels using a cut-off of 3.27 mmol/L.
  • Fig. 5A shows a change in iAge® compared to the change in CCL11 for the treated group for individuals with high (blue) or low (grey) baseline iAge®.
  • Fig. 5B shows a change in iAge® compared to the change in CCL11 for the untreated group for individuals with high (red) or low (grey) baseline iAge®.
  • Fig. 6A shows the change between the baseline and week 2 values for iAge and each analyte (Eotaxin-1 (CCL11 ), IFNy, Gro-a, MIG, and TRAIL) for the treatment (blue) and non-treatment (green) treated groups.
  • Fig. 6B shows The change between the week 2 and week 4 values are shown for iAge and each analyte (Eotaxin-1 (CCL11), IFNy, Gro-a, MIG, and TRAIL) for the treatment (blue) and non-treatment (green) treated groups.
  • Eotaxin-1 CCL11
  • IFNy IFNy
  • Gro-a Gro-a
  • MIG MIG
  • TRAIL TRAIL
  • Fig. 7 shows a graphic representation of an exemplary guided-auto- encoder.
  • a method for reducing systemic chronic inflammation (SCI) in a subject that includes administering an effective amount of a composition to a subject is described.
  • the subject may be a mammal, and more particularly a human.
  • the subject may have low-density lipoprotein (LDL) cholesterol levels of at least about 3 mmol/L.
  • the LDL cholesterol level may be between about 3 mmol/L to about 5 mmol/L.
  • the LDL cholesterol level is at least about 3 mmol/L, about 3.1 mmol/L, about 3.2 mmol/L, about 3.3 mmol/L, about 3.4 mmol/L, about 3.5 mmol/L, about 3.6 mmol/L, about 3.7 mmol/L, about 3.8 mmol/L, about 3.9 mmol/L, or at least about 4 mmol/L.
  • LDL cholesterol level may be at least about 3.25 mmol/L, about 3.26 mmol/L, about 3.27 mmol/L, about 3.28 mmol/L, about 3.29 mmol/L, or at least about 3.3 mmol/L.
  • the subject may have a biological age (also referred to as an iAge® score) of at least about 45.
  • An iAge® score is calculated using a method and parameters disclosed in U.S. Patent Application Publication 2021/0109109 published April 15, 2021 , the entire contents of which are incorporated herein by reference.
  • the biological age is generated using a guided auto-encoder algorithm that assigns weighted scores to the amount of the five biomarkers (Eotaxin-1 (CCL11), IFNy, Gro at, MIG, and TRAIL).
  • the subject’s biological age may be between 45 and 115. In some aspects, the subject’s biological age may be at least about 45, 46, 47, 48, 49, 50, 51 , or 52. In some embodiments, the subject’s biological age may be at least 49.1, 49.2, 49.3, 49.4, 49.5, 49.6, 49.7, 49.8, 49.9, or 50.
  • the iAge® algorithm was generated as follows. Blood and serum samples were collected from 1000 participants. Input data consisted of serum protein micro-flow imaging (MFI) and cell subpopulation frequency data. The data was first log-transformed and then 6 different distributions (Normal, Laplace, LogNormal, log- Laplace, Gamma, log-Gamma) were fit on each input feature using max likelihood estimation (MLE). To identify the best distribution for each feature, a five-fold-cross- validation test was performed for each distribution. A t-test p-value was calculated for the five-fold test likelihoods between normal distribution and other distribution.
  • MFI serum protein micro-flow imaging
  • MLE max likelihood estimation
  • Immune protein data 50 cytokines, chemokines and growth factors: MIG, TRAIL, IFNG, EOTAXIN (i.e. , CCL11), GROA, IL2, TGFA, PAM, MIP1A, LEPTIN, IL1B, LIF, IL5, IFNA, IL4, NGF, HGF, VEGF, FGFB, TGFB, MCSF, PDGFBB, IL7, GMCSF, IL12P40, IL8, SCF, GCSF, CD40L, MIP1B, IL12P70, RESISTIN, IFNB, RANTES, TNFA, MCP1 , IL17F, ENA78, IL1 RA, IL10, IP10, IL13, IL1A, IL15, ICAM1 , TNFB, IL6, MCP3, VCAM1, and FASL) available for all 1001 subjects were used and ex vivo signaling responses to cytokine stimulation data (84
  • prediction analysis of microarrays was used to create a classifier in a training set with subsequent validation in a test set.
  • Prediction analysis of microarrays is a statistical technique that creates a phenotype- specific “nearest shrunken centroid” for classification, and can be used to compare the levels of each immune feature across immunotypes. This is done by a balanced 10-fold cross-validation in a training set, which enables one to choose a threshold that minimizes classification errors.
  • This method makes one important modification to standard nearest centroid classification; it “shrinks” each of the immunotype centroids toward the overall centroid for all immunotypes, which confers an advantage since it makes the classifier more accurate by reducing the effect of the noisy features.
  • the comparison in the levels of serum proteins or signaling responses of specific immunotypes was done by self-contained test of modified Fisher's combined probability on the raw data.
  • Metabolic gene modules analysis A module analysis is performed on the metabolic genes from a sub-cohort of 394 patients. There were 851 genes that overlapped with the metabolic gene set. Agglomerative clustering was used with 50 clusters on the standardized log-transformed metabolic gene expression levels. For each cluster, the Spearman's correlation coefficient was calculated and p-value was obtained between all the gene expression level and patients' age.
  • Auto-encoder Given the input data vector x, an auto-encoder aims to reconstruct the input data vector x.
  • An auto-encoder with L encoding layers and L decoding layers has depth of L were considered, and each layer has fixed number of hidden nodes m.
  • the output of Ith hidden layer is defined as hi(x).
  • the number of nodes in layer 1 is mi.
  • the input into the Ah layer of the network is defined as:
  • Wi is a real value weight matrix of mi-1 by mi and bi is a vector of length mi-i.
  • the output of Ith hidden layer is:
  • a guided auto-encoder aims to reduce both the reconstruction loss and predictive loss. Given the input x, a side-phenotype y and an auto-encoder /AE, the guided-auto-encoder incorporates a predictive function on the coding layer:
  • a is a real value number between 0 and 1 that is called the guidance- ratio.
  • An example guided-auto-encoder with depth 2 and width 3 is shown in Fig. 7.
  • Optimization method ADAM was used to minimize objective. By choosing different guidance-ratio(s), different level(s) of balance can be reached between prediction loss and reconstruction loss.
  • GENE Guided Auto-Encoder
  • the subject may have an LDL cholesterol level of at least about 3 mmol/L or an iAge® of at least about 45. Alternatively, the subject may have an LDL cholesterol level of at least about 3 mmol/L and an iAge of at least about 45. The subject may have an iAge® of at least 49 or an LDL cholesterol level of at least 3.2 mmol/L. Alternatively, the subject may have an iAge® of at least 49 and an LDL cholesterol level of at least 3.2 mmol/L.
  • Reducing SCI refers to reducing the expression level of proteins associated with inflammation.
  • a reduction in the expression level of proteins associated with inflammation can be demonstrated by comparing the expression levels of proteins in a subject before administering the composition and after administration of the composition.
  • the reduction in expression level of proteins associated with inflammation may be detectable after administering the effective amount of the composition every day to a subject for at least one week, at least two weeks, at least three weeks, or at least four weeks.
  • the method may reduce the expression level of Eotaxin-1 (i.e., CCL11 ), IFNy, Gro-a, MIG, or TRAIL in a subject.
  • the method may reduce the expression level of CCL11 and at least one other protein selected from the group consisting of IFNy, Gro-a, MIG, and TRAIL.
  • the subject When the expression level of CCL11 , IFNy, Gro-a, MIG, or TRAIL is reduced in a subject, the subject’s biological age may also reduce. Additionally, once the expression level of proteins associated with inflammation are reduced, a subject’s biological age may be reduced.
  • the subject’s biological age may reduce by about one year, about two years, about three years, or about four years based on the iAge ® algorithm. In some embodiments, a subject’s biological age reduces by at least about one year, at least about two years, at least about three years, or at least about 4 years.
  • the method may treat or prevent disease-associated conditions such as neuroinflammation, neurodegeneration, or psychiatric disorders.
  • the method may be used to lower LDL cholesterol to treat or prevent disease associated with central nervous system pathophysiology.
  • the composition may be provided in a form for oral consumption by the subject.
  • the composition may be provided as a powder capable of being encapsulated such as in a biodegradable capsule.
  • the composition may also be provided as a loose powder capable of being added or incorporated into foodstuff or beverages. Additionally, the composition may be incorporated into a foodstuff or a beverage prior to being administered to a subject.
  • the effective amount of the composition is the minimum amount needed to reduce systemic chronic inflammation in a subject.
  • the effective amount may be capable of reducing the biological age and/or reducing the expression level of proteins associated with inflammation in the subject.
  • the effective amount of the composition may be administered in a single administration or provided in total over several administrations, such as two, three, or four times a day.
  • the effective amount may be about 2 g to about 5 g total for a single day of beta-glucan, which may be divided over several administrations (two, three, four, or five) throughout the day.
  • the effective amount of beta-glucan provided to a subject in a single day may be at least about 2 g.
  • the effective amount of beta-glucan provided to a subject in a single day may be between about 2 g to about 5 g, about 2 g to about 6 g, about 3 g to about 6 g, about 3 g to about 5 g, or about 3 g to about 4 g.
  • the effective amount of avenanthramides provided to a subject in a single day may be at least 0.5 mg.
  • the effective amount of avenanthramides provided to a subject in a single day may be between about 0.5 mg to about 3 mg, about 1 mg to 3 mg, or about 1 mg to about 2 mg.
  • the composition may include beta-glucan, avenanthramides, phenols, or a combination of such.
  • the source of beta-glucan, avenanthramides, or phenols may be provided from natural or synthetic sources.
  • the composition may have beta- glucan and at least one additional component selected from avenanthramides or phenols.
  • the composition includes beta-glucan, avenanthramides, and phenols.
  • the composition may contain at least about 0.75 g of beta-glucan.
  • the composition may contain about 1.0 g, about 1.5 g, about 2.0 g, about 2.5 g, about 3.0 g, about 3.5 g, about 4 g, about 4.5 g, or about 5 g of beta- glucan.
  • the composition may have between about 0.75 g to about 10 g, about 1 g to about 8 g, or about 2 g to about 5g of beta-glucan.
  • the composition has about 0.75 g, about 1 g, about 1.5 g, about 2 g, about 2.5 g, about 3 g, about 3.5 g, about 4 g, about 4.5 g, about 5 g, about 5.5 g, about 6 g, about 6.5 g, about 7 g, about 7.5 g, about 8 g, about 8.5 g, about 9 g, about 9.5 g, or about 10 g.
  • the composition may have about 3 g of beta-glucan.
  • the composition may contain avenanthramides.
  • the composition may include at least about 0.5 mg of avenanthramides.
  • the composition includes at least about 0.5 mg, at least about 1 mg, at least about 1.5 mg, or at least about 2 mg of avenanthramides.
  • the composition may include between about 0.5 mg and about 2.0 mg of avenanthramides.
  • the composition has about 0.90 mg, about 0.95 mg, about 1.0 mg, about 1.05 mg, about 1.10 mg, about 1.15 mg, about 1.20 mg, about 1.25 mg, about 1.30 mg, about 1.35 mg, about 1.40 mg, about 1.4 mg, or about 1.50 mg.
  • the composition may contain 1.10 mg, 1.11 mg, 1.12 mg, 1.13 mg, 1.14 mg, 1.15 mg, 1.16 mg, 1.17 mg, 1.18 mg, 1.19 mg, or 1.20 mg of avenanthramides.
  • the avenanthramides may include the A, B, and/or C forms.
  • the percentage by weight of avenanthramide A may range from about 1% to about 98% of the total avenanthramides percentage by weight.
  • the percentage by weight of avenanthramide B may range from about 1% to about 98% of the total avenanthramides percentage by weight.
  • the percentage by weight of avenanthramide C may range from about 1% to about 98% of the total avenanthramides percentage by weight.
  • avenanthramide A, B, and C may be present in the composition in about equal amounts of 33.3% by weight.
  • the composition may include phenolics such as Avenanthramide A, B, and/or C, Ferulic acid, Caffeic acid, Sinapic acid, gallic acid, 4-hydroxybenzoic acid, 2,4-dihydroxybenzoic acid, 4-hydroxyphenyl acetic acid, vanillic acid, 4- hydroxybenzaldehyde, homovanillic acid, syringic acid, p-coumaric acid, vanillin, Salicylic acid, syringaldehyde, sinapic acid, 3-5, dichloro-4-hydroxybenzoic acid, and o-coumaric acid, or such a combination.
  • phenolics such as Avenanthramide A, B, and/or C, Ferulic acid, Caffeic acid, Sinapic acid, gallic acid, 4-hydroxybenzoic acid, 2,4-dihydroxybenzoic acid, 4-hydroxyphenyl acetic acid, vanillic acid, 4- hydroxybenzaldehyde, homovanillic acid, syring
  • the composition may have at least about 20 mg of total phenolics.
  • the composition may have at least about 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg,
  • the composition may contain between about 20 mg to about 65 mg, about 30 mg to about 55 mg, or about 40 to about 50 mg of total phenolics.
  • the composition includes 46.0 mg, 46.1 mg, 46.2 mg, 46.3 mg, 46.4 mg, 46.5 mg, 48.7 mg, 46.8 mg, 46.9 mg, or 47 mg of total phenolics.
  • the composition may include at least about 2 g of beta-glucan or at least about 45 mg of total phenolics.
  • the composition may include about 2.5 g of beta- glucan and at least about 40 mg of total phenolics.
  • the composition includes at least 3 g of beta-glucan and at least 46 mg of total phenolics.
  • the effective amount of the composition may include at least about 3 g of beta-glucan, at least about 2.6 mg total phenolics, and at least about 1.14 mg of avenanthramides per day provided to the subject.
  • the effective amount may be administered at least once a day, or divided to be administered twice a day, three times a day, four times, or five times per day. Alternatively, the composition may be administered every-other day.
  • the method may include providing the effective amount of beta-glucan per day for at least about 1 week, about 2 weeks, about 3 weeks, or at least about 4 weeks.
  • the effective amount of beta-glucan per day may be administered based on a dosing regimen.
  • the dosing regimen may occur for about one week to about 8 weeks, about two weeks to about 8 weeks, about 2 weeks to about 6 weeks, or about 2 weeks to about 4 weeks.
  • a subject may be administered a composition three times a day to provide a total amount of beta-glucan of 3 g over the course of that day.
  • the three times a day administration may occur during the length of a dosing regimen of at least about one week, at least about 2 weeks, at least about 3 weeks, at least about 4 weeks, or at least about 5 weeks.
  • a subject orally consumes the composition containing an effective amount of beta-glucan and avenanthramides each day for a dosing regimen that occurs for the rest of the subject’s life.
  • the composition may be provided as a plant based material having partially hydrolyzed starch.
  • the partially hydrolyzed starch may comprise at least about 50% of the total starch content.
  • the hydrolyzed starch molecules may have an average molecular weight of no more than 3.4 x10 6 (optionally, 3.0x10 6 , 2.5x10 6 , 2.0x10 6 , 1.8x10 6 , 1.7x10 6 , 1.6x10 6 , 1.5x10 6 , 1.4x10 6 , 1.37x10 6 ) Dalton, or equal to about 3.6x10 6 to about 1.0x10 6 .
  • the composition is formed from oat bran having partially hydrolyzed starch.
  • the composition may be an oat bran concentrate (commercially available as SoluOBC, PepsiCo Inc.) or a partially hydrolyzed oat flour.
  • an oat flour may be combined with other ingredients and an enzyme (e.g., alpha-amylase) to partially hydrolyze the starch in the oat flour, while still maintaining the whole grain status of the oat.
  • the mixture may be heated to between about 120° F. and about 200° F.
  • the mixture may be mixed in a vessel such as an extruder.
  • the enzyme is deactivated in the extruder to form the partially hydrolyzed oat flour.
  • the partially hydrolyzed oat flour may be processed further such as addition of flavorings or stabilizers.
  • the advantage of the partially hydrolyzed starch in the composition is that it can be easily incorporated into a beverage or a foodstuff for administering to a subject.
  • a whole oat flour starting mixture and a suitable enzyme solution in a mixer sometimes called a pre-conditioner
  • the enzyme-treated mixture is then subjected to an extrusion process to gelatinize, hydrolyze, and cook the oat flour mixture.
  • a suitable starting mixture is prepared by combining the whole oat flour with other desired ingredients.
  • a typical starting mixture contains whole oat flour and granulated sugar. Maltodextrin and/or at least one antioxidant may also be added.
  • the whole oat flour is present in an amount of about 50% to about 100% by weight of the total weight of the starting composition. In further aspects, the whole oat flour is present in amounts of about 80% to about 95% by weight or about 90% to about 95% by weight.
  • the sugar can be any suitable sugar known to those skilled in the art.
  • Non-limiting examples of sugars include sucrose, fructose, dextrose, other sugars known in the art, and combinations thereof.
  • the sugar is present in an amount of about 1 % to about 15% by weight or about 3% to about 15% by weight of the total weight of the starting composition. In further aspects, the sugar is present in amounts of about 3% to about 7% by weight.
  • the maltodextrin may be present in an amount of about 0% to about 15% by weight of the total weight of the starting composition. In further aspects, the maltodextrin is present in amounts of about 3% to about 7% by weight.
  • the antioxidant may be any suitable antioxidant such as mixed natural tocopherols or artificial antioxidant such as BHT and BHA.
  • the antioxidant is present in an amount from 0.1% to 2% by weight. In further aspects, the antioxidant is present in amounts of about 0.25% to about 0.75% by weight.
  • the enzyme may be any suitable enzyme to hydrolyze the starch in the oat flour and does not change or adversely affect the beta-glucan that is present in the oat flour.
  • Suitable enzymes include a-amylase in the range of about 0.01% to about 0.5% by weight, for example about 0.1% to about 0.2% by weight.
  • the a-amylase used may be Validase 1000 L having approximately 1 ,000,000 MWU/g (MWU — Modified Wohlgemuth Unit).
  • Whether the beta-glucan has changed by the hydrolysis can be determined by any suitable method such as by analyzing the structure of the beta-glucan. This can be done by laser light scattering mass spectroscopy.
  • the enzyme is added to water to form an enzyme water solution. Then the enzyme-water solution is combined with the starting mixture in the pre-conditioner.
  • the starting mixture and enzyme solution is heated to between about 120° F. and about 200° F., in particular to between about 140° F. and about 180° F., e.g. 165° F. for about 3 to 5 minutes to initiate gelatinization of starch.
  • the enzyme then reacts on gelatinized starches to break down some of the high molecular weight amylopectin starch fractions (having an average molecular weight of 5.8- 6.2x10 6 Dalton) into low molecular weight amylopectin starch fractions (having an average molecular weight of 1.7-2.0x10 6 Dalton).
  • the starting mixture and enzyme solution may be mixed in any suitable vessel such as a high speed mixer that permits liquid to be added to free-flowing flour.
  • the output is a free-flowing wetted flour mixture having a moisture content of about 25 to about 40 % by weight.
  • the residence time is the time sufficient to obtain the desired result and typically 1 to 5 min.
  • the enzyme-treated mixture is subsequently added to an extruder (continuous cooker) to gelatinize, hydrolyze, and cook the starch.
  • the mixture resides in the extruder for a time sufficient to gelatinize and cook the starch, but not long enough to dextrinize or otherwise modify the starch to void the whole grain aspect, generally at least 1 minute, typically, about 1 to about 1.5 minutes, to form a dough.
  • the material is heated from an initial inlet temperature to a final exit temperature in order to provide the energy for starch gelatinization.
  • Starch gelatinization requires water and heat.
  • the gelatinization temperature range for oats is 127° F. to 160° F. (53-71° C.). If the moisture is less than about 60% then higher temperatures are required.
  • Heat may be applied through the extruder barrel wall such as with a jacket around the barrel through which a hot medium like steam, water or oil is circulated, or electric heaters imbedded in the barrel.
  • the extrusion occurs at barrel temperatures between 140° F. and 350° F., for example between 175° F. and 340° F., more specifically about 180° F. to about 300° F.
  • Heat is also generated within the material by friction as it moves within the extruder by the dissipation of mechanical energy in the extruder, which is equal to the product of the viscosity and the shear rate squared for a Newtonian fluid. Shear is controlled by the design of the extruder screw(s) and the screw speed. Viscosity is a function of starch structure, temperature, moisture content, fat content and shear. The temperature of the dough increases in the extruder to approximately 212° F. and 300° F.
  • Low shear is applied to the mixture in the extruder. As the enzyme has preconditioned the starch, high shear is not required for this process. High shear makes it difficult to control the degree of hydrolysis. It can also increase the dough temperature excessively, which can overcook it resulting in too much cooked grain flavor. It is noted that the barrel temperature and the dough temperature may be different.
  • the process balances limiting the dough temperature to avoid too much cooked grain flavor and to keep the enzyme active.
  • the process is balanced such that the dough temperature rises to a sufficient temperature to deactivate the enzyme.
  • Such temperatures are at least 280° F., generally 212° F. to 300° F.
  • a low shear extrusion process is characterized relative to high shear extrusion by high moisture and a low shear screw design versus low moisture and a high shear screw design.
  • Any suitable extruder may be used including suitable single screw or twin screw extruders. Typical, but not limiting, screw speeds are 200-350 rpm.
  • the resulting product may be pelletized using a forming extruder and dried, typically to about 1.5 to about 10% by weight, for example 6.5 to 8.5% by weight, moisture content.
  • the pellets may be granulated to a max 5% through a US 40 screen.
  • the particle size of the resulting granulated product is about 10-500 microns, for instance, about 1-450 microns, more particularly about 30-420 microns.
  • Jet milling may be used to mill the pellets produced in accordance with aspects of the present disclosure. Jet milling creates ultrafine particles.
  • jet milling reduces the particle size of the pelletized soluble oat flour to less than about 90 micron, for example, less than about 50 microns, such as about 46 microns.
  • alternative milling processes can be used to reduce the particle size or micronize the flour to, 0.5-50 microns, such as between 10 to 50 microns.
  • the resulting soluble oat flour includes beta glucan soluble fiber, such as beta-1 , 3-glucan, beta-1 , 6-glucan, or beta-1 , 4-glucan or mixtures thereof.
  • beta glucan may also be added as approved by the FDA.
  • the oat flour preferably contains at least about 3% to 5% or about 3.7% to 4% by weight of beta glucan.
  • the oat flour containing liquid, semi-solid, or solid product contains 0.1% to about 1.5% by weight of beta glucan, or about 0.8% to 1.3% by weight of beta glucan. Other amounts of beta glucan are also useful.
  • the soluble oat flour disperses in less than about 5 seconds in a liquid media at 25° C.
  • the soluble oat flour prepared in accordance with the process described above may be utilized in a variety of products such as: ready-to-drink (RTD) beverages such as dairy-based beverages and juice-based beverages; powders such as for cold and hot instant beverages, instant pudding, custards, mousses, or gelatin, or as an additive to smoothies or shakes for example; dairy products such as yogurt, ice cream, oat-milk, and processed cheeses such as cream cheese; bakery products such as cookies, muffins, breads, pizza crust, bagels, cakes, crepes, and pancakes; ready-to-eat (RTE) snacks such as pudding, fruit leather, and fruit gel snacks; starters or side dishes such as soups (including, without limitation instant soups and ready-to-eat soups) and congee; seasoning mixes, dressings, and sauces; grain-based foods such as upma and hummus; meat-based foods such as meat balls; polenta; and fillings for food products such as mousse, cream, and f
  • the soluble oat flour may also be used as texture modifiers for bakery products or as a replacement for gums, such as guar gum, for instant oatmeal products. Moreover, the soluble oat flour may be used as a fat replacer in products such as cream-based dips. This list is not all-inclusive and one skilled in the art would recognize that the soluble oat flour may be added to other beverages and food products in accordance with the invention. [00106] It was discovered that the use of the soluble oat flour prepared in accordance with the method described above provides unexpected processing improvements and properties over unprocessed oat flour or soluble oat flour prepared by other methods.
  • oat flour used in RTE or RTD products is typically pasteurized or sterilized in order to kill microorganisms that could cause disease or spoilage. This high heat process ensures that the flour is safe and healthy to consume. Such pasteurization and sterilization cannot be easily done on dry flour. Hence, prior to pasteurization or sterilization, the oat flour needs to be completely hydrated to ensure appropriate heat transfer through the oat flour during the kill step. Full hydration and complete gelatinization of the oat flour are desired to ensure the viscosity of the product will not dramatically increase during further processing.
  • Oat flour is typically hydrated by dispersing the oat flour in water and heating the slurry using an appropriate time and temperature combination that results in starch gelatinization. Typically the temperature is 90° C. and the time to hydrate fully is at least 25 minutes. Lower hydration temperatures will require longer times. Then the slurry needs to be cooled down to blend the other ingredients. Then the oat flour slurry may be pasteurized or sterilized by any suitable means such as High Temperature Short time (HTST) pasteurization or Ultra High Temperature (UHT) sterilization. Pasteurization or sterilization is a necessary step for RID or RTE liquid or semi-solid foods.
  • HTST High Temperature Short time
  • UHT Ultra High Temperature
  • soluble oat flour made in accordance with the process described above hydrates without the need of a lengthy heating process of standard or typical oat flour.
  • the quality of the oats is maintained, that is the integrity of the oat flour is maintained throughout the process.
  • the temperature may be around chilled to room temperature, typically 4 to 30° C. reducing the total processing time by 1.5 hours.
  • the amount of soluble oat flour in the water is 2% to 10% by weight, or 3% to 9% by weight, or 4% to 8% by weight.
  • the flour may be further processed to prepare the RTE or RTD product.
  • the soluble oat flour slurry has a much lower viscosity compared to standard or typical oat flour slurry.
  • the standard oat flour produced a much higher viscosity than soluble oat flour especially at higher concentrations of oats.
  • the viscosity of the soluble oat flour slurry at 8% by weight oats is lower than the viscosity of oat flour at 4% by weight oat concentration.
  • Such improved viscosity and hydration results were not expected and has thus allowed the soluble oat flour to be used in products to provide better properties such as better hydration and mixing properties, particularly without the need of elevated temperatures.
  • the viscosity of hydrated soluble oat flour in water in amounts of 2% to 10% by weight will generally ranges from 100 to 1600 cP at 24° C.
  • high shear mixing must be used with the hydrated flour prior to adding to beverage ingredients, to reduce viscosity. Because of the relatively low viscosity of the soluble oat flour, there is no need for such a high shear mechanical process step to reduce viscosity driven by starch. Gentle mixing is sufficient.
  • benefits of using soluble oat flour for beverages instead of typical oat flour include simplified manufacturing processes and less capital investment for heating, mixing and cooling equipment.
  • Soluble oat flour is very effective in dairy beverages because no high temperature heating is required. As discussed above, typically high temperature and time is involved in oat flour hydration. If one wants to use typical oat flour in a dairy beverage, it is recommended to hydrate the oat flour in water because heating fluid milk to the high temperatures required for hydration results in cooked milk flavors. To be able to produce a beverage with high concentration of dairy components, the dairy components must be added as a dairy powder.
  • soluble oat flour allows hydration to occur directly in the fluid milk, producing a product with better sensorial properties, for instance, a fresher flavor is associated with the product since the cold milk has not been subjected to a severe heat hydration treatment and therefore does not have the cooked notes commonly associated with heat treating milk. Attention is drawn to U.S. Ser. No. 13/547,733 which is hereby incorporated by reference in its entirety, which describes the benefits of hydrolyzed oat flour in dairy beverages.
  • Soluble oat flour may also be used in juice beverages. Soluble oat flour can be hydrated in the juice at ambient temperatures or cold temperatures.
  • the juice may be any suitable juice or juice/puree combination. Suitable juices may be acidic or non-acidic, fruit, vegetable, or combinations thereof.
  • Non-limiting examples of juices and purees include, Acai, Aloe Vera Juice, Apple Apricot Nectar, Bancha, Beet, Black Cherry, Black Currant, Blackberry, Blueberry, Boysenberry, Carrot, Celery Coconut, Cranberry, Cucumber, Elderberry, Gogi Berry, Grape, Grapefruit, Kiwi, Strawberry, Tomato, Raspberry, Lemon, Lime, Mango, Orange, Papaya Nectar, Passion fruit, Pear, Pineapple, Plum, Pomegranate, Potato, Prune,
  • a method of reducing systemic chronic inflammation (SCI) in a subject comprising: administering an effective amount of a composition to provide about 2 g to about 5 g of beta-glucan and about 1 mg to about 2 mg of avenanthramides to the subject, wherein the subject has a biological age of about 45 to about 115, and wherein the subject has an LDL cholesterol level of at least 3 mmol/L.
  • SCI systemic chronic inflammation
  • Clause 2 The method of clause 1 , wherein the composition is provided in a form for oral consumption by the subject.
  • Clause 3 The method of clause 1 and 2, wherein the composition is provided as a capsule, beverage, foodstuff, or a powder capable of being added to a beverage or foodstuff.
  • Clause 4 The method of clauses 1 to 3, wherein the composition is administered once, twice, three, four, or five times per day to the subject resulting in a total administration of at least about 2 g of beta-glucan and at least about 1 mg of avenanthramides to the subject.
  • Clause 5 The method of clauses 1-4, wherein the composition comprises at least about 50% hydrolyzed starch molecules of a total starch content, and wherein the hydrolyzed starch molecules have an average molecular weight of no more than 3.4 x 10 6 Dalton.
  • Clause 6 The method of clause 5, wherein the composition is formed from oat bran.
  • Clause 7 The method of clauses 1 to 6, wherein the composition contains at least 0.75 g of beta-glucan.
  • Clause 8 The method of clauses 1 to 7, wherein the composition is administered in a dosing regimen that occurs for at least two weeks, at least three weeks, or at least four weeks. [00125] Clause 9. The method of clauses 1 to 8, wherein the biological age is reduced by at least two years.
  • Clause 10 The method of clauses 1 to 9, wherein the SCI may be diagnosed based on the expression levels of certain biomarkers.
  • a method of reducing systemic chronic inflammation (SCI) in a subject comprising: administering an effective amount of a composition to provide about 2 g to about 5 g of beta-glucan and about 1 mg to about 2 mg of avenanthramides to the subject, wherein the subject has a biological age of about 45 to about 115, wherein the subject has an LDL cholesterol level of at least 3 mmol/L, and wherein the reduction in SCI may be measured by showing a reduction in the expression level of one or more biomarkers in the subject after administering the composition compared to an expression level of biomarkers before administering the composition.
  • SCI systemic chronic inflammation
  • Clause 15 The method of clauses 12 to 14, wherein the composition is provided as a capsule, beverage, foodstuff, or a powder capable of being added to a beverage or foodstuff.
  • Clause 16 The method of clauses 12 to 15, wherein the composition is administered once, twice, three, four, or five times per day to the subject resulting in a total administration of at least about 2 g of beta-glucan and at least about 1 mg of avenanthramides to the subject.
  • Clause 17 The method of clauses 12 to 16, wherein the composition comprises at least about 50% hydrolyzed starch molecules of a total starch content, and wherein the hydrolyzed starch molecules have an average molecular weight of no more than 3.4 x 10 6 Dalton.
  • Clause 18 The method of clauses 12 to 17, wherein the composition is formed from oat bran.
  • Clause 19 The method of clauses 12 to 18, wherein the composition contains at least 0.75 g of beta-glucan.
  • Clause 20 The method of clauses 12 to 19, wherein the composition is administered in a dosing regimen that occurs for at least two weeks, at least three weeks, or at least four weeks.
  • Clause 21 The method of clauses 12 to 20, wherein the biological age of the subject is reduced by at least two years.
  • SoluOBC soluble oat bran concentrate
  • PepsiCo Inc. soluble oat bran concentrate
  • More information about the process to produce SoluOBC is provided in U.S. Patent Publication Serial No. 2017/0273337, published September 28, 2017, now U.S. Patent No. 11 ,172,695 issued November 16, 2021 ; and U.S. Patent No. 9,510,614 issued December 6, 2016, the contents of which are hereby incorporated in their entirety.
  • SoluOBC includes oats that have been processed to partially hydrolyze the starch, the fiber, or both.
  • the Inflammatory Age (iAge®) test (Edifice Health Inc.) was utilized to analyze the biomarkers. Additional information about the Inflammatory Age test is provided in U.S. Patent Application Publication 2021/0109109 published April 15, 2021, the entire contents of which are incorporated herein. Individuals with elevated baseline iAge® and LDL cholesterol exhibited a benefit from the treatment.
  • a double-blinded placebo-controlled interventional study was conducted in 191 healthy male and female patients (38% male, 62% female) ranging from 21 to 65 years of chronological age (the average age was 48) with moderate to elevated LDL-cholesterol levels. The study was conducted over four weeks with blood sampling every two weeks by standard venipuncture.
  • Table 1 provides the components of each sachet.
  • iAge® composed of 5 core proteins CCL11 (aka Eotaxin-1), IFN-g, GRO-a, CXCL9 and TRAIL.
  • Normalized mean fluorescence intensity (MFI) values for each plate were prepared by setting values below the 5 th percentile to the 5 th percentile of the plate and those values above the 95 th percentile were set to the 95 th percentile of the plate. These values were normalized using control serum samples from eleven individuals, both male and female, spanning the chronological ages of 23 - 83 years old.
  • iAge® was derived for all study participants using the machine learning algorithms as discussed above using the normalized MFI values.
  • the systemic chronic inflammation (SCI) index was calculated for each individual from the empirical cumulative distribution of iAge® in the study population from the same decade as the individual.
  • EXAMPLE 3 Statistical Analysis [00141] Samples were grouped by treatment. Change in the inflammatory biomarkers or iAge® at week two from baseline and at week four from week two were compared using a one-tailed pairwise t-test. The least absolute shrinkage and selection operator (LASSO) machine learning algorithm was implemented using the elastic net module in R and used to train a model on age, sex, ethnicity, and other measured baseline traits to predict responders to treatment in the treated group and untreated group. The predictive power of the known and measured attributes in this model is derived from the variable coefficients of the LASSO analysis. A responder has a decrease in iAge® from baseline to week two.
  • LASSO least absolute shrinkage and selection operator
  • variable with the largest coefficient in the LASSO model was used to calculate the optimal cut point that individuals are responders to the treatment using cutpointR. Responders were identified within the treatment group as the difference in iAge® at week two from baseline starting at zero and decreasing by one until the area under the curve no longer increased. Similarly, those with high iAge® at baseline were used to calculate the optimal cut point for LDL-cholesterol level at baseline, which was used to identify additional responders to the treatment.
  • EXAMPLE 5 Baseline iAge® Predicts Effectiveness of SoluOBC Treatment.
  • the trend observed in the reduction of iAge® in the treated group can be used to classify predicted responders and predicted non-responders to the treatment.
  • the Least Absolute Shrinkage and Selection Operator (LASSO) regression was employed, a standard machine learning approach largely utilized for predictive tasks and feature selection.
  • the LASSO regression imposes a penalty to the regression coefficients, such that small coefficients are shrunk to zero and only the most relevant features are selected.
  • the changes in iAge for each subject in the study were calculated and a total of 39 baseline features including subject’s demographics, blood biomarkers for cardiovascular health and lipid fractions, liver function, metabolism and inflammation were used as input (predictor) variables (see Example 3).
  • Elevated iAge® and circulating LDL have been shown to independently contribute to accelerated cardiovascular pathology.
  • a baseline iAge® was identified and used to apply an unbiased approach to divide the 191 participants into those with low and high baseline iAge® with change in iAge® at week two as the output variable.
  • cutpointR a standard method largely utilized in diagnostic testing that automatically selects optimal outpoints for a given outcome variable (see Example 3) was used. The optimal separation of responders and non-responders to SoluOBC was observed at an iAge® value of 49.6 years.
  • EXAMPLE 7 Changes in iAge® induced by SoluOBC are mediated by a decrease in CCL11.

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Abstract

L'invention concerne une méthode de réduction d'une inflammation chronique systémique chez un sujet par l'administration d'une composition pouvant réduire le taux d'expression de biomarqueurs inflammatoires.
PCT/US2022/038704 2021-07-28 2022-07-28 Méthode de réduction d'une inflammation chronique systémique liée à l'âge Ceased WO2023009744A1 (fr)

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CA3224611A CA3224611A1 (fr) 2021-07-28 2022-07-28 Methode de reduction d'une inflammation chronique systemique liee a l'age
MX2024001124A MX2024001124A (es) 2021-07-28 2022-07-28 Metodo de reduccion de inflamacion cronica y sistemica relacionada con la edad.
AU2022320711A AU2022320711A1 (en) 2021-07-28 2022-07-28 Method of reducing age-related systemic chronic inflammation
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